tbuckley/cabot-search huggingface dataset:
P15.07.A Predicting sites of local tumour progression - what should be our imaging biomarker?
Authors: R C Mayrand, Y Wei, C Li, R Perry Mayrand, Y Wan, N Simon, R Sinha, S Sravanam, S J Price
Journal: Neuro-Oncology (2022)

Abstract Background Glioblastoma is the most aggressive primary brain tumour diagnosed in adults. Despite intensive treatment of maximal safe resection and chemoradiotherapy, the prognosis remains grim due to invasive tumour cells. Current treatment and standard imaging methods are highly limited in terms of managing these invasive cells as they are often located outside the area of surgical resection and are generally resistant to chemoradiation. DTI appears to be a promising tool for imaging tumour cell invasion and predicting the site of recurrence especially when decomposed into its anisotropic (q) and isotropic (p) components. The aim of this study is to investigate the sensitivity of imaging biomarkers as predictors of recurrence. Material and Methods All pre-op and recurrence sequences were co-registered to the pre-op post-contrast T1-weighted images as reference. Co-registration of images was performed using FSL and ANTs. The ROIs for 49 patients with a primary diagnosis of GBM were segmented using 3DSlicer. Each voxel was assigned to one of four status: true negative, false negative, true positive and false positive. Sensitivity and specificity between the pre-op ROIs and the progression region were calculated using FSL. The significance of the differences in sensitivity and specificity between the ROIs was computed in MATLAB. Results The sensitivity for the contrast enhancing region was 48.77 ± 26.13 (Mean ± SD) and 62.40 ± 23.07 (Mean ± SD). The abnormal q alone has a significantly greater sensitivity than the contrast enhancing region (t = -2.7327, df = 96, p-value = 0.0075). The sensitivity for the ROI of combined contrast enhancement and abnormal q was 65.86 ± 23.29 (Mean ± SD). There is an even more significant increase in sensitivity when the contrast enhancing ROI is combined with abnormal q region (t = -3.4133, df = 96, p-value = 9.4123e-04) compared to when it is alone. There was no statistical difference in the specificities of the different ROIs. Conclusion Current surgical and radiation volumes focus solely on pre-op contrast enhancement. However, these results suggest that combining the abnormal q with the standard contrast enhancing region is a more sensitive predictor of tumour recurrence than contrast enhancement alone, while still retaining high specificity. The higher sensitivity is an indicator of correct identification of tumour recurrence while the high specificity correctly identifies normal brain, or non-recurrent regions. These results are currently being prospectively assessed in a multi-centre study (PRaM-GBM).
JS09.5.A Is Radiation Dose to Sleep-relevant Brain Structures Associated with Lower Sleep Quality in Adults with Primary Brain Tumors?
Authors: A Amidi, L Haldbo-Classen, J Kallehauge, L Wu, S Lukacova, Y Lassen, R Zachariae, M Hoyer
Journal: Neuro-Oncology (2022)

Abstract Background Sleep plays a central role in optimal brain health and daily functioning, and poor sleep is associated with impaired cognitive functioning and reduced quality of life. Despite improved precision of modern radiotherapy (RT) for brain tumors, radiation to healthy tissue, including brain structures relevant for sleep/wake regulation, is often inevitable. In the present study, we investigate whether radiation dose to sleep/wake-relevant brain structures is associated with poorer patient-reported sleep quality in primary brain tumor patients. Material and Methods Patients who had received RT for non-glioblastoma primary brain tumors between 2006 and 2016 were included. They completed the Pittsburg Sleep Quality Index (PSQI) and mean radiation doses to sleep/wake-relevant structures (i.e., brainstem, thalamus, hypothalamus, and the pituitary and pineal glands) were calculated based on planning CTs and contrast-enhanced MR-images. Mean radiation dose (Dmean) to brain structures were compared between patients with and without impaired sleep outcomes using bootstrapped independent t-tests. Differences with effect sizes (ES, Cohen’s d) exceeding ± 0.3 are reported. Results A total of 78 patients (glioma, grade 1-3 = 28; meningioma = 22, pituitary = 16, other = 12) were included. Median time since RT was 4.6 years (range = 8.4 years). Mean global PSQI score was 5.13 (SD = 3.1). No differences were observed between tumor types, F (3,74) = 0.37, η 2= .02. Clinical sleep disturbance (PSQI &amp;gt; 5) was reported by 37.2% (n=29). Compared with patients without sleep disturbance, those with sleep disturbance had received a higher radiation dose to the pituitary gland, Dmean = 26.11 Gy, SE = 2.59, versus 34.57 Gy, SE = 3.43, ES(d) = - 0.46, 95% CI [-0.93, 0.003]. Furthermore, compared with patients reporting normal sleep latency (SL), those with poor SL had received a higher radiation dose to the pituitary gland, Dmean = 24.55 Gy, SE = 3.71, versus 32.60 Gy, SE = 2.48, ES(d) = - 0.44, 95% CI [-0.90, 0.03], and the brain stem, Dmean = 15.32 Gy, SE = 2.71, versus 20.20 Gy, SE = 2.01, ES(d) = -3.44, 95% CI [-0.80, 0.12]. Finally, compared with patients with a high sleep efficiency (&amp;gt;85%), those with a low sleep efficiency had received a higher radiation dose to the thalamus, Dmean = 18.11 Gy, SE = 2.36, versus 24.55 Gy, SE = 4.43, ES(d) = -0.35, 95% CI [-0.83, 0.15], and the pineal gland, Dmean = 16.20 Gy, SE = 2.48, versus 23.10 Gy, SE = 4.25, ES(d) = -0.36, 95% CI [-0.85, 0.13]. Conclusion The prevalence of clinical sleep disturbances in patients with primary brain tumors was high (37%). Our results indicated that higher radiation doses to the pituitary gland, brain stem, thalamus, and pineal gland may be risk factors for poor sleep quality in patients with a primary brain tumor.
P13.01.A Challenges and Solutions for Establishing a CNS Tumor Registry in Africa
Authors: F Fezeu, C Opara, V Djientcheu, E Fonkem, S Samnick
Journal: Neuro-Oncology (2022)

Abstract Background CNS tumor registries (CTR) has evolved to a key tool for data collection, evaluation of diagnostic and treatment of patients suffering from tumors of the central nervous system (tCNS) in the U.S, but CTR in Africa does not yet exist. In comparison to high-income countries (HIC), many low- and middle-income countries (LMIC) do not yet have national or central CNS tumor registries. Furthermore, appropriate diagnostic steps like MRI and pathological analysis are still scarce in many LMIC. Improving the availability of CTR in resource- limited regions could allow better understanding of some specificities of tCNS including incidence, prevalence, mortality and morbidity. However, CTR, MRI and pathological analysis tend to be costly and thus difficult to implement in the LMIC setting. Material and Methods A review of the current body of literature on tCNS in Africa was conducted using multiple scientific online data bases. Search terms included ,,CNS tumor registry,” “developing countries,” “low and middle income,” and other related terms as starting point for future initiatives. Results It was found that more than 1,3 billion people residing in Africa lack access to a continental CTR. There is no well established standards for reporting tCNS. Most tCNS are still underreported in many countries of Africa. The exact burden of tCNS in Africa is unknown. Although many successful, long-term, initiatives for international neurological and neurosurgical collaborations are published, any CTR of Africa similarly to the Central Brain Tumor Registry of the United States (CBTRUS) is lacking. Conclusion: Disparities in access to care for patients suffering from tCNS have been well published but well established solutions are still under investigations. Partnerships between centers in LMIC and HIC are making progress to better understand the burden of disease in LMIC and to create context-specific solutions for practice in the LMIC setting. Collaboration between the World Health Organisation, national centers for disease control in Africa, departments of neuroscience in LMIC and well established registries like the CBTRUS as well as other interested groups could be meaningful strategical steps to be initiated for the establishment of CTR in Africa. A CTR for Africa could lead to better comprehension of tCNS in Africa, thus facilitate prevention, diagnostic, treatment and research.
P09.04.B The importance of treatment tolerability for people with glioma: registry review and qualitative findings from the COBra Study
Authors: E Baddeley, A Retzer, S Sivell, K Seddon, H Bulbeck, A Nelson, R Adams, R Grant, C Watts, O Aiyegbusi, S Rivera, P Kearns, L Dirven, M Calvert, A Byrne
Journal: Neuro-Oncology (2022)

Abstract Background Gliomas are the commonest form of primary brain tumour, accounting for 80% of malignant brain tumours. Gliomas represent a heterogeneous group of cancers with variable outcomes, traditionally graded from I to IV (least to most aggressive). The poor prognosis of some glioma patients and high symptom burden has led to a growing emphasis on their quality of survival. Maintaining cognitive function, physical function and other health-related quality of life aspects throughout the disease trajectory are key considerations, particularly for patients with aggressive forms of glioma. It is therefore important that glioma intervention studies collect data aligned with patient priorities that enables assessment of the net clinical benefit of treatments and facilitates informed decision-making. In particular, and of increasing recognition, is the importance of monitoring the incidence of adverse events during and after the course of an intervention, and understanding their impact upon patients, and patients’ own assessment of, tolerability. Material and Methods A trial registry review, a systematic review of the qualitative literature and semi-structured interviews with patients and caregivers were undertaken. Outcomes were extracted from these sources to formulate a longlist during the development of a core outcome set for glioma interventional trials (the COBra study). Results The registry review (n=91), systematic review (n=21) and semi-structured interviews (n=19) identified many important outcomes and concepts, one of which was tolerability. Tolerability, adverse events, toxicity or safety was reported to be collected as an outcome in 46 trials. Outcomes related to tolerability were identified from 7 articles included in the systematic review. Themes related to tolerability emerged from the qualitative interviews. These included tolerability of side effects of treatment; trade-offs of side effects versus potential benefits in deciding on, and willingness to, undertake further treatment; and self-directed strategies for coping. Conclusion There is a growing acknowledgement of the importance of treatment tolerability in the wider field of cancer research. In glioma research specifically, its significance is yet to be reflected in outcomes collected in trials. Our qualitative findings indicate tolerability is of high significance to patients and those close to them. Participants reported how their preconceptions and experience of tolerability influenced treatment decisions and treatment uptake. However, outcomes related to tolerability were collected in just over half of trials in our sample. Tolerability and items relating to the patients’ experience of adverse events should be collected and reported in trial findings to reflect patients’ priorities and enable informed treatment decisions.
P18.11.A Active beam scanning proton therapy for large skull base benign meningiomas: long-term results
Authors: D Amelio, L Lo Faro, F Corsini, D Donner, F Chioffi, F Volpin, L Volpin, F Chierichetti, S Sarubbo, D Scartoni
Journal: Neuro-Oncology (2022)

Abstract Purpose To report long-term results of active beam scanning proton therapy (PT) for large skull base benign meningiomas Material and Methods Eighty-two patients (pts) with large skull base meningiomas were treated with PT between April 2015 and December 2021. Median age was 62 years (range, 48-82) while KPS ranged between 60 and 100 (median 90); 60 were female (73%), and 22 were male (27%). Thirty-two pts (39%) had histologically proven World Health Organization (WHO) Grade I tumors. In remaining pts diagnosis was based on the typical imaging appearance of benign meningioma. All patients received PT for residual, progressive or non-operable lesions. Newly diagnosed tumors received total dose of 50 GyRBE (RBE: relative biologic effectiveness) while progressing meningiomas 54 GyRBE. All the treatments were delivered at 2 GyRBE per fraction. All pts were treated with active beam scanning PT using 3 fields with single field optimization technique. Treatment planning was based on morphological magnetic resonance imaging (MRI) with contrast enhancement medium administration. All pts received also 68-Ga-DOTATOC-PET. Gross tumor volume ranged from 21 to 64 cc. Toxicity was assessed according to Common Terminology Criteria for Adverse Events version 4.0. Median follow-up time was 40 months (range, 3-83). Results All pts completed the treatment without breaks. Registered acute side effects include grade 1 (19%) and grade 2 (8%) skin erythema, grade 1 (5%) and grade 2 (5%) alopecia, grade 1 (40%) fatigue, grade 1 (5%) and grade 2 (10%) conjunctivitis, grade 1 (10%) pain, grade 1 (5%) blurred vision, grade 1 (10%) headache, and grade 2 (5%) skin hyperpigmentation. One pts (1%) experienced grade 3 pain. There were no further grade 3 or higher acute toxicities. Registered late side effects include grade 1 (2%) and grade 2 (5%) alopecia, grade 1 (21%) fatigue, grade 1 (5%) and grade 2 (5%) headache, grade 1 (6%) dizziness, grade 1 (3%) blurred vision, grade 1 (3%) and grade 2 (6%) pain, grade 1 (2%) dry eye, and grade 1 (5%) skin hyperpigmentation. Two pts (2%) experienced grade 3 pain. Two further pts (2%) experienced grade 3 optic neuropathy. There were no further grade 3 or higher late toxicities. During follow-up one pts (1%) with cavernous sinus meningioma experienced complete obstruction of intracavernous carotid artery with mild transient symptoms that resolved in few days and brain tissue ischemia detected at MRI (grade 2). Before irradiation this pts already had a meningioma-related near-complete obstruction of the intracavernous carotid artery and received a vascular surgery evaluation. Currently, absolute tumor control is 99%. Moreover, relief of symptoms recorded before irradiation occurred in 40% of pts. Conclusion PT is safe and effective treatment for pts with large skull base benign meningiomas.
Dipeptidyl peptidase-1 inhibition in patients hospitalised with COVID-19: a multicentre, double-blind, randomised, parallel-group, placebo-controlled trial
Authors: Holly R Keir, Merete B Long, Hani Abo-Leyah, Yan Hui Giam, Thenmalar Vadiveloo, Thomas Pembridge, Rebecca C Hull, Lilia Delgado, Margaret Band, Fiona McLaren-Neil, Simon Adamson, Eva Lahnsteiner, Amy Gilmour, Chloe Hughes, Benjamin Jm New, David Connell, Rebecca Dowey, Helena Turton, Hollian Richardson, Diane Cassidy, Jamie Cooper, Jay Suntharalingam, Lavanya Diwakar, Peter Russell, Jonathan Underwood, Alexander Hicks, Davinder Ps Dosanjh, Beth Sage, Devesh Dhasmana, Mark Spears, Aa Roger Thompson, Christopher Brightling, Andrew Smith, Manish Patel, Jacob George, Alison M Condliffe, Amelia Shoemark, Graeme MacLennan, James D Chalmers
Journal: The Lancet Respiratory Medicine (2022)
P05.02.A 18F-FACBC PET/MRI in diagnostic assessment of gliomas
Authors: L K Pedersen
Journal: Neuro-Oncology (2022)

Abstract Background and Theory MRI and histopathological tissue sampling are routinely done as part of the diagnostic work-up of patients with glioma. MRI provides anatomical images with high resolution and excellent soft-tissue contrast. But this modality has limitations in identifying tumor grade, true tumor extension and differentiate viable tumor tissue from treatment induced changes. PET can provide quantitative information of cellular activity and metabolism, and may therefore have additional value compared to MRI alone. Objective The aim of this study was to find the sensitivity of [18F]FACBC PET in gliomas, and evaluate if PET imaging with this tracer can improve differentiation between low-and high-grade gliomas. Methods Patients with suspicion of primary (n=19) or recurrent gliomas (n=8) were recruited to this study from St. Olavs hospital, Trondheim University Hospital, Trondheim, and from the University Hospital of North Norway, Tromsø. PET acquisitions (30-45 min post injection) using the amino acid radiotracer [18F]FACBC (3 MBq/kg) were performed simultaneously to MRI acquisitions (T1 with and without contrast, FLAIR, and UTE for attenuation correction. The sensitivity of [18F]FACBC PET in glioma detection was assessed using histopathology as reference. Tumor-to-background ratios (TBRs) were compared to tumor subtype and grade to assess the diagnostic value of this tracer for glioma diagnostics. Results Histopathology revealed 2 WHO grade 1 gliomas (pilocytic astrocytoma n=1, pilocytic astrocytoma/ganglioglioma n=1), 7 WHO grade 2 gliomas(astrocytoma n=4, oligodendroglioma n=3), 7 WHO grade 3 gliomas(astrocytoma n=5, oligodendroglioma n=2) and 12 WHO grade 4 tumors(astrocytoma n=1, glioblastoma n=11). [18F]FACBC PET provided a sensitivity of 74.1% in the detection of gliomas. PET uptake was observed in all grade 4 tumors, 5/7 grade 3 tumors, 2/7 grade 2 tumors, and all grade 1 tumors. TBRpeak was high with a median value of 9.4 (range: 2.1-34.9) in PET positive tumors. Only tumors with a TBRpeak &amp;gt; 2.0 were detected with [18F]FACBC PET. TBRpeak was highest for grade 1 gliomas with a median value of 20.6, and increased significantly from grade 2 to grade 4 tumors with median values of 1.7 (grade 2), 6.2 (grade 3) and 12.4 (grade 4) (Kruskal-Wallis, p=0.001). Conclusion [18F]FACBC PET demonstrated high uptake in the majority of gliomas, and there was a clear tendency to higher uptake in the higher grade tumors. [18F]FACBC PET may be useful in the differentiation between glioms grades and subtypes. A future study using the same patient data will be performed to evaluate the assessment of [18F]FACBC PET in neurosurgical treatment planning. Image-localized biopsies from different regions of each tumor will be correlated to fused PET/MRI images to evaluate if [18F]FACBC PET can be used to guide surgical resection and to improve accuracy in histopathological tissue sampling.
P11.03.B BXQ-350: Modulating ceramide and Sphingosine-1-Phosphate for anti-tumor activity and potential mitigation of chemotherapy induced peripheral neuropathy
Authors: G H Tapolsky, J C Morris, E Yilmaz, J L Villano, C Muller, R C Curry, III, V K Puduvally, T M Wise-Draper, R Takigiku, R Wesolowski
Journal: Neuro-Oncology (2022)

Abstract Background Sphingolipids are a class of bioactive signaling molecules implicated in multiple cellular processes and molecular pathways. Many publications have indicated that among these sphingolipids, sphingosine-1-phosphate (S1P) is a key sphingolipid that promotes cancer cell survival and proliferation, activates multiple oncogenic pathways, and stimulates immuno-suppressor cell populations promoting a pro-tumoral microenvironment. Many of these publications have also implicated S1P with chemotherapy induced peripheral neuropathy, a debilitating and serious side effect that may impact therapeutic treatments and patient’s quality of life. Material and Methods BXQ-350 is a nanovesicle of Saposin C, an allosteric activator of sphingolipid metabolism, that has broad anticancer activity, potentially in part by lowering systemic S1P levels. BXQ-350 was investigated in a Phase 1 dose-escalation safety study in an all-comer cancer patients with advanced solid malignancies, including CNS tumors (NCT02859857) to determine its safety profile and its potential clinical activity as a single agent in cancer patients. Samples were collected to determine pharmacokinetics and explore potential biomarkers. Results 11 patients (~15% of evaluable patients) with advanced disease had a clinical benefit and amongst these, 8 patients (~11% of evaluable patients) had PFS&amp;gt; 6 months with 2 patients still on study five years after enrollment. Analysis of patient’s samples revealed that BXQ-350 decreases systemic S1P levels in the majority of the patients experiencing a clinical benefit. In addition, several patients with established CIPN spontaneously reported improvements of their symptoms shortly after BXQ-350 administration. Analysis of these patients’ samples also revealed that S1P systemic levels had decreased, as well as pro-inflammatory cytokines associated with CIPN. Conclusion While these results are exploratory and preliminary in nature, they suggest that BXQ-350’s mechanism of action may represent a novel anti-cancer approach that may also mitigate CIPN.
P10.01.A Reversible blood-brain barrier (BBB) disruption by Tumor Treating Fields (TTFields) in a human 3D<i>in vitro</i> model
Authors: E Salvador, A F Kessler, T Köppl, S Schönhärl, M Burek, C Tempel Brami, T Voloshin, M Giladi, R Ernestus, M Löhr, C Förster, C Hagemann
Journal: Neuro-Oncology (2022)

Abstract Background Drug delivery to the central nervous system (CNS) is often impeded by the restrictive nature of the blood brain barrier (BBB). Since many therapeutic molecules are not able to traverse this barrier, the development of new methods to disrupt the BBB is of paramount importance. Tumor Treating Fields (TTFields) are alternating electric fields of low intensity (1-3 V/cm) and intermediate frequency (100-300 kHz), which are approved and effective for the treatment of glioblastoma at a frequency of 200 kHz. We recently demonstrated that TTFields at lower frequencies are able to transiently induce BBB permeability in in vitro and in vivo murine models. Here, we explored whether the transient opening of the BBB by TTFields in our murine systems also translates to a human cell-based 3D model. Material and Methods A three-dimensional BBB model was established by co-culturing primary human brain microvascular endothelial cells (HBMVEC) on a transwell insert together with human pericytes on the bottom of a well-plate. The model was treated with TTFields at 100-300 kHz for 2496 h using the inovitro™ TTFields Lab Bench System (Novocure®). Afterwards, the cells recovered for 24-96 h. In order to analyze the effects of TTFields on barrier integrity and compromise, transendothelial electrical resistance (TEER) of the HBMVEC monolayer was measured before the start of TTFields treatment, immediately after TTFields cessation, as well as 24-96 h after TTFields treatment. Permeability of the barrier was assessed by visualizing the movement of FITC-dextran through the HBMVEC monolayer. In addition, changes in expression and localization of the tight junction protein (TJP) claudin-5 (Cl-5) after application of TTFields were analyzed by fractionated Western-blotting and immunofluorescence (IF) staining, respectively. Results Application of TTFields at all investigated frequencies significantly decreased TEER across the HBMVEC monolayer after as early as 24 h, with the strongest effects seen after 72 h at a TTFields frequency of 100 kHz. TTFields treatment delocalized TJP Cl5 from the cell boundaries to the cytoplasm as evidenced by Western-blots and IF stainings. Restoration of the cell barrier was already measurable as early as 24 h after TTFields cessation and a complete recovery was evident after 48 h. Conclusion These results in a human 3D in vitro model confirm our previous observations from mouse models that TTFields could transiently open the BBB. These fundamental pre-clinical data demonstrate the feasibility of facilitating drug delivery to the CNS via concomitant application of TTFields. This method opens up the prospect of improved drug-based treatment of devastating CNS diseases such as GBM if these results could be translated to the clinical setting in the future.